More than 100 million Americans experience a pain episode that lasts for weeks to years. Annual expenditures related to pain are higher than those for cancer, heart disease, and diabetes combined. One of the most significant indicators of the need for new pain medicines is the opioid epidemic in the US and globally. Essentially, opioids have been overprescribed to treat severe chronic and acute pain and the results have been devastating. Opioid addiction has become an epidemic effecting people from all walks of life. Recently, the CDC estimated that opioid addiction, results in over 70 deaths per day in the United States.
Pain management of severe acute or chronic peripheral pain is a complex issue that impacts the entire nervous system. Basically, an intact central nervous system (CNS) is required for the conscious perception of pain; however, blocking this perception with centrally acting drugs presents a higher risk of adverse effects. The blockade of nociceptive input into the CNS can effectively relieve or markedly attenuate discomfort and pain, revealing the importance of ongoing peripheral input to the maintenance of chronic pain. Thus, as used herein, to “treat pain” is simply meant to relieve or markedly attenuate or alleviate discomfort and pain. Thus, the development of peripherally acting pain management schemes and formulations is highly desired. Szallasi, A., et al., The Vanilloid Receptor TRPV1: 10 Years from Channel Cloning to Antagonist Proof-of-Concept, Nature Revs. Drug Disc., 6: 357-372, 2007; Moran, M. M., et al., Transient Receptor Potential Channels as Therapeutic Agents. Nature Revs. Drug Disc., 10: 601-620, 2011; Woolf, C. J., Overcoming Obstacles to Developing New Analgesics, Nature Medicine, 16: 1241-1247, 2010. Accordingly, there is a current focus on nociceptors: their role in initiating and maintaining pain might present a new very effective target for development of novel pain therapeutic approaches. Szallasi, A., et al., The Vanilloid Receptor TRPV1: 10 Years from Channel Cloning to Antagonist Proof-of-Concept, Nature Revs. Drug Disc., 6: 357-372, 2007; Patapoutina, A., et al., Transient Receptor Potential Channels, Nature Revs. Drug Disc., 8: 55-68, 2009; Vriens, J., et al., Pharmacology of Vanilloid Transient Receptor Potential Cation Channels, Mol. Pharmacol., 75: 1262-1279, 2009; Moran, M. M., et al., Transient Receptor Potential Channels as Therapeutic Agents. Nature Revs. Drug Disc., 10: 601-620, 2011; Woolf, C. J., Overcoming Obstacles to Developing New Analgesics, Nature Medicine, 16: 1241-1247, 2010. The central terminals of nociceptors represent important drug targets as this area contains receptors that can alter neurotransmitter release: e.g. G protein-coupled receptors, GABA receptors and voltage-gated calcium channels can effectively be modulated by existing and well-tested pharmacons
The current understanding of the heterogeneity of mechanisms that contribute to the transition from acute tissue insult to chronic pain and to pain conditions with various underlying pathological status has advanced significantly in the past decade. Caterina, M. J. et al., Molecular Biology of Nociceptors, The Neurobiology of Pain (eds. Hunt, S. & Koltzenburg, M.) 1-33, Oxford Univ. Press, Oxford, 2005; Basbaum, A. I. et al., Molecular Mechanisms of Pain, Cell 139: 267-284, 2009; Kuner, R. Central Mechanisms of Pathological Pain, Nature Medicine, 16: 1258-1266, 2010; Costigan, M., et al., Neuropathic Pain: A Maladaptive Response of the Nervous System to Damage, Annu. Rev. Neurosci. 32: 1-32, 2009; Gold, M. S. and Gebhart, G. F., Nociceptor Sensitization in Pain Pathogenesis, Nature Medicine 16: 1248-1257, 2010.
The fundamental sensations to sense touch and pain originate in peripheral sensory neurons, which possess signaling pathways that translate environmental stimuli into neural activity. Families of ion channel proteins have been identified that serve as sensors for temperature and other noxious stimuli in primary afferent nociceptors, initiating action potentials in the peripheral terminals that ultimately release pronociceptive neurotransmitters from their central terminals to activate secondary, nociceptive spinal cord neurons. Szallasi, A., et al., The Vanilloid Receptor TRPV1: 10 Years from Channel Cloning to Antagonist Proof-of-Concept, Nature Revs. Drug Disc., 6: 357-372, 2007; Patapoutina, A., et al., Transient Receptor Potential Channels, Nature Revs. Drug Disc., 8: 55-68, 2009; Vriens, J., et al., Pharmacology of Vanilloid Transient Receptor Potential Cation Channels, Mol. Pharmacol., 75: 1262-1279, 2009; Moran, M. M., et al., Transient Receptor Potential Channels as Therapeutic Agents. Nature Revs. Drug Disc., 10: 601-620, 2011
Painful peripheral neuropathy is associated with several systemic illnesses (e.g. diabetes, cancer and HIV infection) and motivates approximately 25-50% of all pain clinic visits. Currently, LYRICA® (pregabalin, sold by Pfizer, Inc.) is approved by the FDA in the form of capsules for the management of diabetic neuropathic pain, and its congener gabapentin is similarly useful. Gabapentinoids are effective analgesic agents in neuropathic and inflammatory pain systemically and intrathecally. (Cheng, J K and Chiou, L C, J. Pharmacol. Sci., 100: 471-486, 2006). Recent evidence suggests that these drugs modulate the trafficking step of α2/δ auxiliary subunit of voltage-gated calcium channels from the cell soma to the terminals (Taylor C. P., supra; Hendrich, J., et al., supra; Bauer, C. S., et al., J. Neurosci., 29: 4076-4088, 2009), thereby decreasing exocytosis at the presynaptic terminal. (Christopherson, K. S., et al., Cell, 120: 421-433, 2005; Eroglu, C., et al., Cell, 139: 380-392, 2009. Neely, G. G., et al., Cell, 143: 628-638, 2010; Hoppa, M. B., et al., Nature, 486: 122-126, 2012; Marimoto, S., et al., J. Pharmacol. Sci., 118: 455-466, 2012; Patel, R., et al., J. Neurosci. 33: 1612-1646, 2013). Thus, topical application of gabapentin at the painful area might allow access to both the peripheral and central terminals of nociceptors to produce pain relief (Boardman, L. A., et al., Obst. Gynecol., 112: 579-585, 2008; Plaza-Villegas, et al., Oral Surg, Oral Med Oral Path Oral Radiol., 114: 449-456, 2012; Martinez, J. A., et al., Mol. Pain, 8: 3-20, 2012; Zur, E., Clin. J. Pain, 30: 73-91, 2014).
Molecular biological studies have shown that gabapentin (GBP) binds to an exofacial epitope of the α2/δ-1 and α2/δ-2 auxiliary subunits of voltage-gated calcium channels. (Field M J, et al., Proc Nat'l Acad. Sci. USA, 103: 17537-17542, 2006; Fuller-Bicer G A, et al., Am J Physiol Heart Circ. Physiol., 297: H117-24, 2009; Gee N S, Brown J P, et al., J. Biol. Chem, 271:5768-5776, 1996; Luo, D. Z., et al., J. Neurosci, 21:1868-1875, 2001). The α2/δ-1 subunits are present mainly in presynaptic terminals, and peripheral sensory nerve injury results in the up-regulation of α2/δ-1 in dorsal root ganglion (DRG) neurons (Luo, D. Z., et al., supra; Taylor C. P., Pain, 142: 13-16, 2009), with consequent increase in trafficking of α2/δ-1 to their terminals (Taylor C. P., supra; Hendrich, J., et al., Proc. Natl. Acad. Sci. USA, 105: 3628-3633, 2008). Thus, gabapentin may function therapeutically by blocking new synapse formation, presenting a rationale for its topical application.
Current treatment strategies include use of non-steroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, opioids, cannabinoids, sodium channel blockers, gabapentinoids, tricyclic antidepressants, selective serotonin and norepinephrine reuptake inhibitors and anti-NGF. All of the above pharmacotherapeutic strategies carry the risk of significant side effects. While new pathways, such as the NGF/TrkA, fatty acid amide hydrolase (FAAH) and enkephalinase pathways are explored by utilizing designer inhibitor drugs, only a few to none have succeeded so far to treat severe, chronic and acute pain. However, at this time, there are limited available pharmacotherapeutics or formulations that can specifically target the conditions that are also present in chronic inflammatory, maladaptive and functional pain. There is an unmet clinical need for improved, non-addictive treatments for many painful conditions. Such opportunities include pain relief in a higher percentage of patients, greater magnitude of pain relief and greater benefits for health-related quality of life.
Transdermal delivery of pain medications is an important pharmacological approach selectively targeting the affected areas and primary afferent neurons. Since these neurons serve as the initial generator of noxious impulses, inhibiting their activation or sensitization can prevent subsequent sensitizing central events (e.g. wind-up) and plasticity. Embodiments of the invention relate to transdermal drug delivery formulations that dramatically improve the local tissue delivery of active drugs and consequently carry the potential of improving management of chronic pain with reduced side effects. The compositions and methods described herein show the efficacy of using a topical cream formulation comprising ibuprofen combined with another drug such as gabapentin as active ingredients in well-characterized animal models of chronic pain.
One important part of this invention is the need to have both drugs in the combination, amalgamate in the same tissue at the same time. This is critically important with peripheral pain, especially when targeting the peripheral nerve tissue, including the first synapse. Systemic delivery is generally ineffective in accomplishing this objective. Transdermal delivery, by contrast, can be very effective in delivering both of the combinatorial drugs through the skin and into the peripheral tissue targets at the same time and in the concentrations needed to generate an augmented pain reducing effect.
The transdermal delivery of pain medication ingredients through the skin or other body surfaces is attractive to patients for a variety of reasons. In addition to convenience, transdermal formulations eliminate the “first pass liver effect”, avoid the irritation and stomach bleed of the gastrointestinal tract that often accompany pills and capsules. Furthermore, transdermal delivery can increase the efficiency of a drug by targeting more of it in the tissue where the drug was needed as opposed to general systemic delivery.
Transdermal also has another important advantage in treating peripheral pain. By applying the transdermal compound in the area where it is needed, transdermal can efficiently target the tissue needing treatment and minimize systemic exposure to the drug combination. Of course, for a transdermal drug delivery formulation to be effective, it must be capable of delivering the drug or drug combination through the skin and into the peripheral tissue targets. U.S. Pat. Nos. 9,566,256 and 9,561,174 (both herein incorporated by reference in their entireties) teach a number of technologies that are efficient in delivering drug and drug combinations through the skin and these teaching are incorporated herein.
Thus, an effective treatment system for severe acute or chronic peripheral pain, must include a combination of drugs one chosen from the NSAID class and the other chosen from the gabapentin family delivered into the peripheral target tissue via transdermal technology.